Preclinical Monitoring of Drug Association in Experimental Chemotherapy of Chagas' Disease by a New HPLC-UV Method

Silva, Rodrigo Moreira da; Oliveira, Líliam Teixeira; Silva-Barcellos, Neila Márcia; Souza, Jacqueline de; Lana, Marta de

doi:10.1128/aac.05785-11

Cited by 32 publications

(26 citation statements)

References 22 publications

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“…Workman et al reported a similar C max , 36 g/ml, in mice treated with 78 mg/kg of BNZ (12). In this study, the elimination half-life (t 1/2b ) of BNZ was 2.03 h, which is similar to the values reported by Davanço et al, Moreira da Silva et al, and Workman et al, which were 2.7, 1.6, and 1.6 h, respectively (12,16,18). These short half-lives indicate a high metabolism, which is responsible for low oral bioavailability.…”

Section: Discussionsupporting

confidence: 80%

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Pharmacokinetics and Tissue Distribution of Benznidazole after Oral Administration in Mice

Perin

Silva

Fonseca

et al. 2017

Antimicrob Agents Chemother

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Specific chemotherapy using benznidazole (BNZ) for Chagas disease during the chronic stage is controversial due to its limited efficacy and toxic effects. Although BNZ has been used to treat Chagas disease since the 1970s, few studies about the biodistribution of this drug exist. In this study, BNZ tissue biodistribution in a murine model and its pharmacokinetic profile in plasma were monitored. A bioanalytical high-performance liquid chromatography method with a UV detector (HPLC-UV) was developed and validated according to the European Medicines Agency for quantification of BNZ in organs and plasma samples prepared by liquidliquid extraction using ethyl acetate. The developed method was linear in the BNZ concentration, which ranged from 0.1 to 100.0 g/ml for plasma, spleen, brain, colon, heart, lung, and kidney and from 0.2 to 100.0 g/ml for liver. Validation assays demonstrated good stability for BNZ under all conditions evaluated. Pharmacokinetic parameters confirmed rapid, but low, absorption of BNZ after oral administration. Biodistribution assays demonstrated different maximum concentrations in organs and similar times to maximum concentration and mean residence times, with means of 40 min and 2.5 h, respectively. Therefore, the biodistribution of BNZ is extensive, reaching organs such as the heart and colon, which are the most relevant organs affected by Trypanosoma cruzi infection, and also the spleen, brain, liver, lungs, and kidneys. Simultaneous analyses of tissues and plasma indicated high BNZ metabolism in the liver. Our results suggest that low bioavailability, instead of inadequate biodistribution, could be responsible for therapeutic failure during the chronic phase of Chagas disease.

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Section: Discussionsupporting

confidence: 80%

“…However, several methods have been described for BNZ quantification in animal and human plasma, urine, and milk (12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22). To evaluate BNZ biodistribution, a bioanalytical method was developed to determine its quantification in mouse tissues, including spleen, brain, heart, colon, liver, lung, and kidney.…”

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confidence: 99%

Pharmacokinetics and Tissue Distribution of Benznidazole after Oral Administration in Mice

Perin

Silva

Fonseca

et al. 2017

Antimicrob Agents Chemother

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“…As few as 13 doses of BZ or NFX given at 5 day intervals, or 9 doses of BZ if preceded by a 5 day course of POS treatment performed equally as well as 40 daily doses of BZ or NFX. This result was unexpected based upon the documented half-life of BZ of 1-2 hours in mice [31,32] and the presumption that the effectiveness of BZ depended on sustaining a concentration above the minimum inhibitory concentration [33]-hence the reason for giving BZ twice daily in humans where its half-life is approximately 12 hours [29]. This result is particularly significant because some of the side effects of BZ treatment can be eliminated with a reduction in the cumulative dose of BZ [10].…”

Section: Discussionmentioning

confidence: 99%

New, Combined, and Reduced Dosing Treatment Protocols Cure Trypanosoma cruzi Infection in Mice

Bustamante¹,

Craft²,

Crowe³

et al. 2013

Journal of Infectious Diseases

127

173

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The development of treatment protocols with reduced toxicity and equivalent or improved efficacy for Trypanosoma cruzi infection is a priority. We tested the effectiveness of benznidazole (BZ), nifurtimox (NFX), other prospective drugs in intermittent and combined treatment protocols to cure T. cruzi infection initiated with susceptible and drug-resistant parasite strains. A 40-day course of BZ, NFX, or the oxaborale AN4169 cured 100% of mice, whereas posaconazole (POS), and NTLA-1 (a nitro-triazole) cured approximately 90% and 20% of mice, respectively. Reducing the overall dosage of BZ or NFX by using an intermittent (once every 5 days) schedule or combining 5 daily doses of POS with 7 intermittent doses of BZ also provided approximately 100% cure. T. cruzi strains resistant to BZ were also found to be resistant to other drugs (POS), and extending the time of treatment or combining drugs did not increase cure rates with these isolates. Thus, dosing schedules for anti-T. cruzi compounds should be determined empirically, and compounds targeting different pathways may be combined to yield effective therapies with reduced toxicity. This work also suggests that standard treatment protocols using BZ and NFX may be significantly overdosing patients, perhaps contributing to the adverse events.

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“…Una de las manifestaciones clíni-cas más importantes en los adultos es la miocardiopatía infecciosa, llegando a ser la tripanosomiasis americana la principal causa de esta condición a nivel mundial; mientras que en los niños es frecuente la aparición de miocarditis y meningoencefalitis (8) . Se estima que alrededor de 10 mil personas mueren anualmente debido a las manifestaciones crónicas de la enfermedad de Chagas, siendo las alteraciones cardiacas y gastrointestinales las principales causas de muerte (7,9) .…”

Section: Introductionunclassified

“…Los factores de riesgo para el desarrollo de esta condición han sido ampliamente establecidos, entre ellos, residir o incluso proceder de América Latina, vivir en condiciones precarias o ser transfundido con unidades que contengan cualquier forma del parási-to (8,10) . El estado inmunológico de los pacientes es un factor determinante en el curso de la enfermedad, ya que este parásito puede llegar a comportarse como un agente oportunista de alta agresividad en individuos con inmunodeficiencias, causando cuadros clínicos como meningoencefalitis, miocarditis o, en casos muy severos, fallas multisistémicas (11) .…”

Section: Introductionunclassified

Tripanosomiasis americana, una mirada desde el tratamiento

et al. 2016

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ResumenLa tripanosomiasis americana o enfermedad de Chagas es una infección parasitaria causada por el parásito flagelado Trypanosoma cruzi, cuyo principal vector es un insecto de la clase hemíptera conocido como triatomino. La quimioterapia, adicional a un control oportuno de vectores y rigurosidad en el control de las transfusiones, son los elementos más importantes para el manejo de esta parasitosis. En la actualidad, el mercado farmacéutico solo ofrece nifurtimox y benznidazol como opciones terapéuticas, y a pesar de que se han obtenido resultados satisfactorios con el uso de estos medicamentos en fases agudas de la enfermedad, tripanosomiasis congénita y accidentes de laboratorio, la efectividad en las fases crónicas es notoriamente menor. Además, ambos fármacos generan ciertos efectos adversos que deben ser tenidos en cuenta por el personal de la salud, antes de iniciar el debido manejo de esta enfermedad. El objetivo del presente artículo es revisar el estado actual del tratamiento farmacológico de la tripanosomiasis americana, buscando resumir los nuevos avances terapéuticos y dar a conocer las limitaciones de los mismos debido a sus efectos adversos. Palabras clave. Enfermedad de Chagas; Tripanosomiasis; Terapéutica. Abstract American trypanosomiasis or Chagas disease is a parasitic infection caused by the flagellate parasite Trypanosoma cruzi, whose main vector is an insect of the Hemiptera class, called triatomine. Chemotherapy, in addition to an appropriate vector control and a rigorous control of transfusions, are the most important strategies for the management of this parasitosis. Currently, the pharmaceutical market only offers nifurtimox and benznidazole as treatment options, and although satisfactory results have been obtained with the use of these drugs in either acute stages of the disease, congenital trypanosomiasis and laboratory accidents, its effectiveness in the chronic phases is significantly smaller. In addition, both drugs produce some side effects that must be taken into account by health workers, before starting the proper management of the disease. The aim of this article is to review the current state of the American trypanosomiasis treatment, in order to summarize the new advances in therapeutics and to introduce their limitations due to adverse effects. Keywords. Chagas Disease; Trypanosomiasis; Therapeutics. An INTRODUCCIÓNLa tripanosomiasis americana, también conocida como enfermedad de Chagas, es la infección parasitaria más importante en las Américas, en donde afecta de 8 a 10 millones de personas (1)(2)(3) . Es causada por el parásito flagelado Trypanosoma cruzi, cuyo principal vector es un insecto de la clase hemíptera conocido como triatomino. El parási-to también puede ser adquirido por el consumo de alimentos y bebidas contaminadas, trasplantes de órganos, transfusiones sanguíneas y por vía congénita, siendo estas vías menos frecuentes (1,4) .En el curso natural de la enfermedad es posible diferenciar tres fases clínicas: una fase aguda, usualmente asintomá-tica, que t...

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Preclinical Monitoring of Drug Association in Experimental Chemotherapy of Chagas' Disease by a New HPLC-UV Method

Cited by 32 publications

References 22 publications

Pharmacokinetics and Tissue Distribution of Benznidazole after Oral Administration in Mice

Pharmacokinetics and Tissue Distribution of Benznidazole after Oral Administration in Mice

New, Combined, and Reduced Dosing Treatment Protocols Cure Trypanosoma cruzi Infection in Mice

Tripanosomiasis americana, una mirada desde el tratamiento

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